The genus Lyssavirus is a member of the Rhabdoviridae family within the order Mononegavirales (viruses with a single-stranded, negative sense genome). Lyssaviruses are the etiological agents of rabies encephalitis in warm-blooded animals and humans (Tordo et al., “Lyssaviruses” In Fauquet et al. eds. Virus taxonomy: the classification and nomenclature of viruses. The 8th Report of the International Committee on Taxonomy of Viruses. San Diego: Oxford Academic, 2006, pages 623-629; World Health Organization Expert Consultation on Rabies, 5-8 Oct. 2004, first report, World Health Organization Technical report series 931, Geneva: World Health Organization, 2005, pages 15-19). Lyssavirus species include rabies virus (RABV; genotype 1), Lagos bat virus (LBV; genotype 2), Mokola virus (MOKV; genotype 3), Duvenhage virus (DUVV; genotype 4), European bat lyssavirus-1 (EBLV-1; genotype 5), European bat lyssavirus-2 (EBLV-2; genotype 6), Australian bat lyssavirus (ABLV; genotype 7) and four additional species isolated from bats in central Asia and Russia (Aravan virus—ARAV; Khujand virus—KHUV; Irkut virus—IRKV; and West Caucasian bat virus—WCBV) (Kuzmin et al., Emerg. Infect. Dis. 14(12):1887-1889, 2008; Weyer et al., Epidemiol. Infect. 136:670-678, 2007; Kuzmin and Rupprecht, “Bat rabies” In Rabies, 2nd Edition, New York, Academic Press, 2007, pages 259-307, Jackson and Wunner, eds.).
Based on phylogeny, immunogenicity and virulence of lyssavirus isolates, two lyssavirus phylogroups have been proposed (Badrane et al., J. Virol. 75:3268-3276, 2001). The division into phylogroups generally correlates with the pattern of vaccine cross-protection observed for lyssaviruses (Badrane et al., J. Virol. 75:3268-3276, 2001; Hanlon et al., Virus Res. 111:44-54, 2005; Nel et al., Expert Rev. Vaccines 4:553-540, 2005). Phylogroup 1 includes genotypes 1, 4, 5, 6 and 7, as well as ARAV, KHUV and IRKV (Kuzmin et al., Virus Res. 97:65-79, 2003; Kuzmin et al., Virus Res. 111:28-43, 2005; Hanlon et al., Virus Res. 111:44-54, 2005). Currently available commercial vaccines and biologicals are considered to be effective against infections of viruses from this phylogroup (Nel et al., Expert Rev. Vaccines 4:553-540, 2005). However, these vaccines and biologics for rabies do not offer full protection against infection with viruses outside of lyssavirus phylogroup 1 (i.e., genotypes 2 and 3). In addition, WCBV is recognized as the most divergent lyssavirus and exhibits limited relatedness to genotype 2 and 3 viruses. Previous studies have demonstrated little or no cross-neutralization of anti-RABV sera with WCBV (Botvinkin et al., Emerg. Infect. Dis. 9:1623-1625, 2003; Hanlon et al., Virus Res. 111:44-54, 2005).
Thus, a need exists to develop a rabies vaccine that can protect against a broad spectrum of lyssaviruses, particularly WCBV and lyssaviruses of genotypes 2 and 3.